Figure 6: ERRα-driven metabolic adaptations restore detoxification capacity.

(a) Quantification of the absolute and relative levels of GSH/GSSG in pSKBr3 or LRSKBr3 cells on lapatinib and C29 treatment. (b) Quantification of the absolute and relative levels of intermediate metabolites of the glutathione synthesis pathway in pSKBr3 or LRSKBr3 cells on lapatinib and C29 treatment. (c) Schematic diagram illustrating glutathione metabolism and ROS detoxification in relation to other metabolic pathways. Green, downregulated on C29 treatment in LRSKBr3 cells; red, upregulated; blue, unchanged. (d) Normalized cell index curves representing the survival of lapatinib-resistant SKBr3 cells on treatment with the antioxidant compounds N-acetylcysteine (NAC; 500 μM) or Trolox (500 μM) in presence or absence of the ERRα inhibitor C29. (e) Live imaging (top panel) and quantification (bottom panel) of lapatinib-resistant SKBr3 cells stained using DCFDA to detect ROS in the presence of lapatinib alone or in combination with the ERRα inhibitor C29. All error bars are s.d. from three independent experiments, statistical significance is calculated using two-tailed unpaired t-test; *P<0.05; **P<0.01.